Corneal transplantation is the most common form of solid tissue transplantation, with over 30,000 keratoplasties performed each year in the U.S. First-time recipients of corneal allografts can expect a 90% success rate, even though keratoplasty is usually performed without the use of HLA typing or systemic immunosuppressive drugs. The unparalleled success of keratoplasty is attributed to the immune privilege of the eye, which down-regulates the immune responses to the histocompatibility antigens on the corneal transplant. This project will evaluate the roles of two important populations of T regulatory cells that are believed to endow the corneal transplant with immune privilege and promote its long-term survival. Even though corneal transplants enjoy a remarkable success, immune rejection remains the leading cause of corneal graft failure. Anecdotal reports from clinicians suggest that patients with allergic conjunctivitis have a significantly greater risk for rejecting their corneal transplants. We recently confirmed this observation in a mouse model of penetrating keratoplasty and found that allergic conjunctivitis produces a remarkable adjuvant effect that results in a heightened immune response to the histocompatibility antigens on the corneal transplant, which culminates in a profound increase in the incidence and tempo of corneal allograft rejection. This project will characterize the basis for this heightened immune response to the corneal histocompatibility antigens that occurs in hosts with allergic conjunctivitis. Studies will also test the hypothesis that other forms of allergy, such as allergic asthma, also increase the risk for the immune rejection of corneal transplants by enhancing systemic immune responses, even in distant organs. Understanding the basis for the role of T regulatory cells in promoting immune privilege of corneal transplantation will provide a basis for developing new immunosuppressive agents for improving corneal graft survival in high risk hosts. The incidence of allergic diseases continues to grow and thus, is an increasingly important risk factor for corneal graft survival. This project will provide important insights into understanding the basis for the allergy-associated risk for corneal graft rejection and determine if other forms of allergy should also be considered as risk factors for corneal allograft survival. These studies will lead to improved strategies for re-establishing immune privilege of corneal transplants and offsetting the untoward effects of allergic diseases on the fate of corneal transplants.